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Definity, Optison Black Box Warning Revised

May 14, 2008 | Parker Waichman Alonso LLP

The Food & Drug Administration (FDA) is watering down its warning about the possible risks of Definity and Optison, micro-bubble contrast agents used during ultrasounds of the heart to enhance images during a procedure called echocardiography.  Though the labels of the contrast agents will continue to bear a black box warning about the risk of serious, and sometimes fatal cardiopulmonary reactions, the FDA has dropped a ban on giving the agents to acutely ill patients, such as those with congestive heart failure.  The FDA also changed monitoring requirements for the drugs.  The warning had called for monitoring all patients for 30 minutes after they receive the agents, but the new warning says only patients with pulmonary hypertension or unstable cardiopulmonary conditions need to be monitored.

Definity, marketed by Bristol Myers Squibb, and Optison, distributed by General Electric, consist of microscopic gas-filled spheres that sharpen ultrasound pictures.  According to the FDA, there have been more than 200 reports of serious cardiac reactions involving the use of Definity and Optison.  In October 2007, the FDA said that it knew of at least 11 deaths associated with the administration of either Definity or Optison.  Four of those fatalities occurred either during infusion or within 30 minutes following the administration of the contrast agent.   The FDA said that most of the serious but non-fatal reactions also occurred in the same time frame.

As a result of these reports, the FDA requested that the labeling on Definity and Optison be modified to include a black box warning about the cardiac problems associated with these agents.    A black box warning is the FDA’s strictest type of warning.  But many cardiologists questioned the restrictions the FDA placed on Definity and Optison.  At least one prominent cardiologist said that the black box warning was added to the ultrasound contrast agents without a formal examination of the risks and benefits of using them.

The FDA's decision to drop the ban on micro-bubble contrast agents  for acute patients  came after a study was published that indicated the risk from the dyes might not be as serious as first thought.  That study, which was presented at the April meeting of the American College of Cardiology, examined the clinical outcomes of nearly 18,000 patients who received ultrasound contrast agents during an echocardiogram and compared their results to those from a group of approximately 6,000 patients who did not need to receive contrast agents.

To test the safety of contrast agents, the researchers looked at the short-term (within 30 minutes of the infusion) and long-term (within 24 hours) outcomes and noted any serious adverse events or deaths. Of the nearly 18,000 individuals to receive the contrast agents, not one experienced an adverse event within 30 minutes. One death and three non-fatal heart attacks occurred within 24 hours; however these could not be attributed to the contrast agents.

According to The Wall Street Journal, cardiologists are applauding the FDA's move. The previous restrictions meant physicians had to used other diagnostic methods — including angiograms and an ultrasound technique that involves going in through the patient’s throat — that come with their own risks.